Tricalcium Phosphate Coarse Particle Compositions and Methods for Making the Same

ABSTRACT

Methods for preparing a tricalcium phosphate coarse particle composition are provided. Aspects of the methods include converting an initial tricalcium phosphate particulate composition to hydroxyapatite, sintering the resultant hydroxyapatite to produce a second tricalcium phosphate composition and then mechanically manipulating the second tricalcium phosphate composition to produce a tricalcium phosphate coarse particle composition. The subject methods and compositions produced thereby find use in a variety of applications.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.12/568,531 filed on Sep. 28, 2009 and application Ser. No. 12/328,720filed Dec. 4, 2008; the disclosures of which applications are hereinincorporated by reference.

INTRODUCTION

Calcium phosphate cements find use as structural materials in theorthopedic and dental fields. Such cements are typically prepared bycombining a dry component(s) and a liquid to form a flowable paste-likematerial that is subsequently capable of setting into a solid calciumphosphate product. Materials that set into solid calcium phosphatemineral products are of particular interest as such products can closelyresemble the mineral phase of natural bone and are susceptible toremodeling, making such products extremely attractive for use inorthopedics and related fields. While a large number of differentcalcium phosphate cement formulations have been developed, there is acontinued need for the development of yet more advanced formulations.

SUMMARY

Methods for preparing a tricalcium phosphate coarse particle compositionare provided. Aspects of the methods include converting an initialtricalcium phosphate particulate composition to hydroxyapatite,sintering the resultant hydroxyapatite to produce a second tricalciumphosphate composition and then mechanically manipulating the secondtricalcium phosphate composition to produce a tricalcium phosphatecoarse particle composition. The subject methods and compositionsproduced thereby find use in a variety of applications.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows an X-ray diffraction of material synthesized from ProcessA, Process B, and Process C, as described in greater detail in theExperimental Section, below.

FIG. 2 a shows an SEM micrograph of particles obtained from Process Athat are 38-106 μm. FIG. 2 b shows an SEM micrograph of particlesobtained from Process A that are 106-212 μm.

FIG. 3 a shows calcite morphology. FIG. 3 b shows monetite morphology.

FIG. 4 shows an SEM micrograph of material obtained from Process A afterthe blending step.

FIG. 5 a shows an SEM micrograph of particles obtained from Process Bthat are 38-106 μm. FIG. 5 b shows an SEM micrograph of particlesobtained from Process B that are 106-212 μm.

FIG. 6 shows an SEM micrograph of material obtained from Process Bbefore the firing step.

FIG. 7 shows an SEM micrograph of material obtained from Process B afterthe firing step.

FIG. 8 shows an SEM micrograph of material obtained from Process B afterthe firing step.

FIG. 9 a shows an SEM micrograph of particles obtained from Process Cthat are 38-106 μm. FIG. 9 b shows an SEM micrograph of particlesobtained from Process C that are 106-212 μm.

DETAILED DESCRIPTION

Methods for preparing a tricalcium phosphate coarse particle compositionare provided. Aspects of the methods include converting an initialtricalcium phosphate particulate composition to hydroxyapatite,sintering the resultant hydroxyapatite to produce a second tricalciumphosphate composition and then mechanically manipulating the secondtricalcium phosphate compostiion to produce a tricalcium phosphatecoarse particle composition. The subject methods and compositionsproduced thereby find use in a variety of applications.

Before the present invention is further described, it is to beunderstood that this invention is not limited to particular embodimentsdescribed, as such may, of course, vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Methods recited herein may be carried out in any order of the recitedevents which is logically possible, as well as the recited order ofevents.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, the preferredmethods and materials are now described.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

All publications mentioned herein are incorporated herein by referenceto disclose and describe the methods and/or materials in connection withwhich the publications are cited.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

In further describing the subject invention, the subject methods will bedescribed first, followed by a description of the compositions producedthereby, kits for use in preparing the same and methods for using thesubject compositions in methods of hard tissue, e.g. bone repair.

Tricalcium Phosphate Coarse Particle Compositions and Methods of Makingthe Same

As summarized above, the invention provides methods of preparingtricalcium phosphate coarse particle compositions. In methods of theinvention, an initial tricalcium phosphate composition is firstconverted to hydroxyapatite. Tricalcium phosphate is a compound withformula Ca₃(PO₄)₂. It is also known as calcium orthophosphate, tertiarycalcium phosphate, tribasic calcium phosphate, or “bone ash”. Tricalciumphosphate has β-phase (low temperature phase), γ-phase (high pressurephase), and α-phase (high temperature phase). In certain embodiments,tricalcium phosphate used in the present methods has an alpha crystalform or a beta crystal form. Alpha-tricalcium phosphate (α-TCP) is ahigh-temperature and beta-tricalcium phosphate (β-TCP) is alow-temperature polymorph

In a certain instances, the initial tricalcium phosphate particulatecomposition is obtained from commercial sources. VITOSS® tricalciumphosphate composition is composed of β-TCP and can be purchased fromOrthovita (Malvern, Pa.). Other commercial sources of tricalciumphosphate include Curasan (Research Triangle Park, N.C.), Depuy Spine(Mountain View, Calif.), and Teknimed (L'Union, France).

Alternatively, the initial tricalcium phosphate composition may besynthesized denovo. Any convenient synthesis protocol may be employed.In one instance, the initial tricalcium phosphate composition isprepared by combining DCPA, calcite and water to produce a pastecomposition; sintering the paste composition to produce a sinteredproduct; and then mechanically disrupting the sintered product toproduce the initial tricalcium phosphate particulate composition. DCPAis dicalcium phosphate, anhydrous and can be purchased commercially fromMutchler Inc. (Harrington Park, N.J.), Fuji Health Science (Burlington,N.J.), and JRS Pharma (Patterson, N.J.). Calcite is a carbonate mineraland a stable polymorph of calcium carbonate (CaCO₃). Calcite can bepurchased commercially from Ashirwad Minerals and Marbles (India) andBritex Enterprises (Delhi, India),

In methods of the invention, the initial tricalcium phosphatecomposition is converted to hydroxyapatite. While any convenientprotocol may be employed, in some instances conversion of the initialtricalcium phosphate composition to hydroxyapatite is accomplished bycombining the initial tricalcium phosphate composition with an alkalimetal phosphate solution. Suitable alkali metal counterions includesodium, potassium, and lithium. Suitable alkali metal phosphatesolutions of interest include sodium phosphate, sodium phosphatedibasic, sodium phosphate monobasic, potassium phosphate, potassiumphosphate dibasic, and potassium phosphate monobasic. In a certaininstance, the alkali metal phosphate solution is a sodium phosphatesolution, such as NaH₂PO₄.

The intial tricalcium phosphate composition and alkali metal phosphatesolution may be combined using any convenient protocol. As such, avolume of the solution may be combined with an amount of the dry initialtricalcium phosphate composition with mixing to produce a pastecomposition which sets into hydroxyapatite. Mixing may be manual orautomated. Drying may occur at room temperature or at elevatedtemperatures. Following production of the hydroxyapatite, the resultanthydroxyapatite is then milled or pelletized. Accordingly, in someembodiments the hydroxyapatite is milled before sintering. Millingtechniques include use of jet mill, disc mill, blender, homogenizer,serrated disc type agitator, pearl mill, high speed impeller mill, ballmill, sand mill, attritor, rotor stator mixer and the like. In someinstances, the hydroxyapatiite is disc milled before sintering. In yetother embodiments, the hydroxyapatite is pelletized before sintering.Pelletizing is the process of compressing or molding of a product intothe shape of a pellet and can be performed with a pellet mill. A pelletmill is a type of mill used to create cylindrical pellets from a mixtureof dry powder and a wet ingredient. The pellets are made by compactingthe material into many small holes in a die. The die is usually roundand the pellets are pushed from the inside out. Pellet mills combinesmall materials into a larger, homogeneous mass. The pelletizing processcan include the use of heat and pressure.

Following conversion of the initial tricalcium phosphate composition tohydroxyapatite and subsequent processing as desired (e.g., milling orpelletizing as reviewed above), the resultant hydroxyapatite is sinteredto produce a second tricalcium phosphate composition. Sintering is amethod where material is heated below its melting point until itsparticles adhere to each other. Sintering may be performed atatmospheric or elevated pressure, as desired. In certain embodiments,sintering occurs at temperatures ranging from 1300-1500° C., such as attemperatures of 1300° C., 1350° C., 1400° C., 1425° C., 1450° C., and1500° C. In one instance, sintering occurs at 1400° C. In anotherinstance, sintering occurs at 1425° C. In another instance, sinteringoccurs at 1450° C.

As summarized above, sintering results in the production of a secondtricalcium phosphate composition. The resultant second tricalciumphosphate composition is then mechanically manipulated to produce atricalcium phosphate coarse particle composition. Mechanicalmanipulation may vary, where mechanical manipulation may be achieved bydisc milling and sieving. Pulverizing systems with one or more disc millassemblies as known in the art may be employed. In some instances, thepulverizing system includes feeding input material to the disc mill,carrying ground material from the disc mill to a sorting module,transporting acceptable ground material to a ground material collectionarea, and recirculating unacceptable ground material to a disc mill forfurther grinding. A disc mill can include a spindle, a flywheel, arotating disc blade, a stationary disc blade, a means for cooling thestationary disc blade (e.g., a waterjacket), a means for introducing airinto the mill, and a means for adjusting a gap between facing cuttingsurfaces of the disc blades. An example of a pulverizing system using adisc mill is described in WO 2004/071666

Other methods of mechanical manipulation include blender, homogenizer,serrated disc type agitator, pearl mill, high speed impeller mill, ballmill, sand mill, attritor, rotor stator mixer and the like. Specificspeed characteristics depend on equipment, blade configuration, size,etc., but can be determined readily by one skilled in the art.

Methods of the invention are high yield methods with respect to theproduction of coarse tricalcium phosphate particles. The methods of theinvention can yield a composition that is 50% or more coarse particles,such as 60% or more coarse particles, including 80% or more coarseparticles by number.

Coarse tricalcium phosphate particles produced in accordance withmethods of the invention are particles that are 20 μm in diameter orlarger, such as ranging in size from 38 to 212 μm in diameter. Incertain embodiments, the method produces a tricalcium phosphate coarseparticle composition that comprises particles ranging in size from 38 to106 μm. In another embodiment, the method produces a tricalciumphosphate coarse particle composition that comprises particles rangingin size from 106 to 212 μm.

The method produces tricalcium phosphate coarse particles comprising analkali metal ion in an amount ranging from 1500 to 2500 ppm. In certainembodiments, the particles comprise an alkali metal ion in an amountranging from 1500 to 2400 ppm, 1600 to 2400 ppm, 1600 to 2200 ppm, or1600 to 2000 ppm. The alkali metal ion can be sodium, potassium, orlithium. The alkali metal ion can come from the alkali metal phosphatesolution that is used to form hydroxyapatite.

Coarse particle compositions having a high amount of coarse particles,e.g., 50, 60, 80% or more as reviewed above, may be further processed asdesired. For example, the desired tricalcium phosphate coarse particles(for example those particles ranging in size from 38 to 212 μm indiameter) may be separated from the remainder of the composition usingany convenient separation protocol, such as sieving, etc.

Calcium Phosphate Cements and Methods of Using the Same

Coarse tricalcium phosphate particles of the invention find use in avariety of different applications where tricalcium phosphate is desiredas a reactant. One application of interest includes the use of thetricalcium phosphate coarse particle compositions in calcium phosphatecements formulated for use in medical and dental applications.

In some instances, the tricalcium phosphate coarse particles of theinvention are present in a cement that is made up of a dry reactioncomposition which includes both the coarse particles of the invention,e.g., as described above, and a fine particle component. In these typesof cements, the dry reactants include the a tricalcium phosphate coarseparticle composition that has mean particle size that is at least 2times larger than the mean particle size of the fine particlescomponent, where the mean particle size of coarse particle component maybe 20 μm or larger, 30 μm or larger, 40 μm or larger (as determinedusing the Horiba LA-300 laser diffraction particle sizer (Version 3.30software for Windows 95)(Irvine, Calif.)), such as 50 μm or larger, 100μm or larger, 150 μm or larger, 200 μm or larger, where the particlesize of the tricalcium phosphate coarse particle component population(also referred to herein as a coarse particle size population) may rangefrom 10 to 500 μm, such as from 25 to 250 μm. In certain instances, theparticles of this component can range in size from 38 pm to 212 pm, suchas from 38 μm to 106 μm or 106 μm to 212 μm.

As indicated above, also present in cements of these embodiments is afine particle composition component which is a calcium and/or phosphatedry reactant having a mean particle size (as determined using the HoribaLA-300 laser diffraction particle sizer (Version 3.30 software forWindows 95)(Irvine, Calif.)) of less than 8 μm and a narrow particlesize distribution (which is referred to below as a fine particle sizepopulation). As such, the dry reactant component of the cement, whichmay include one or more distinct dry reactants, includes a reactant thathas a mean particle size of less than 8 pm and a narrow particle sizedistribution. The mean particle size of this reactant may vary, rangingin representative embodiments from 1 to 7 μm, such as from 1 to 6 μm,including from 1 to 5 μm, where the mean particle size in certainembodiments may be 1, 2, 3 and 4 μm, where in certain embodiments themean particle size is 3 μm.

There is also a narrow particle size distribution. By narrow particlesize distribution is meant that the standard deviation of the particlesthat make up the particular reactant population (as determined using theHoriba LA-300 laser diffraction particle sizer (Version 3.30 softwarefor Windows 95)(Irvine, Calif.)) does not exceed 4.0, and in certainrepresentative embodiments does not exceed 3.0, e.g., does not exceed2.5, including does not exceed 2.0 μm. The fine particle component isfurther characterized in that the mode (as determined using the HoribaLA-300 laser diffraction particle sizer (Version 3.30 software forWindows 95)(Irvine, Calif.)) does not exceed 8.0, and in certainrepresentative embodiments does not exceed 6.0, e.g., does not exceed 5,including does not exceed 3 μm.

In certain embodiments, the fine particle composition is a calciumphosphate compound having a calcium to phosphate ratio ranging from 1.0to 2.0, including from 1.33 to 1.67, such as 1.5. In certainembodiments, the calcium phosphate compound is a tricalcium phosphate,such as α- and β-tricalcium phosphate, where in certain embodiments, thetricalcium phosphate is α-tricalcium phosphate.

In certain embodiments, the amount of the fine particle reactant in thedry reactant component is greater than the total amount of otherreactants that may be present in the dry reactant component, such as thecoarse particle reactant as described herein. In these embodiments, themass ratio of the fine particle reactant to the total mass of the dryreactants of the dry reactant component may range from 1 to 10, e.g.,from 9 to 6, such as from 9 to 7, including from 9.5 to 8.5.

The ratios or relative amounts of each of the disparate fine and coarseparticle reactants in the dry reactant component is one that providesfor the desired calcium phosphate product upon combination of the dryreactant component with the setting fluid and subsequent setting. Incertain embodiments, the overall ratio of all of the disparate calciumand/or phosphate compounds in the dry reactants in terms of the calciumto phosphate ration in the dry reactant component ranges from 4:1 to0.5:1, usually from 2:1 to 1:1 and more usually from 1.9:1 to 1.33:1.

The fine and coarse particle reactants may be made up of the same ordifferent compounds, e.g., the same or different calcium minerals, suchas the same or different calcium phosphate minerals. For example, incertain embodiments of interest, the dry reactant component includesboth coarse and fine particles of the same calcium containing mineral,e.g., α-tricalcium phosphate. In yet other embodiments, a portion, ifnot all of the coarse population of particles is made up of one or moredifferent calcium containing compounds as compared to the compoundmaking up the fine particle size population. For example, in certainembodiments, one may have a fine particle reactant made up of a firstcalcium containing compound, e.g., α-tricalcium phosphate particles, anda coarse particle reactant made up of a second calcium containingcompound that differs in some way from the compound making up the firstpopulation, e.g., in terms of phase, molecular formula, solubility,radiopacity, etc. In certain embodiments, the fine and coarse particlereactants will be made up of different phases of the same calciumcontaining compound, such as the same calcium phosphate containingcompound. For example, the coarse and fine particle size reactants couldboth be made up of tricalcium phosphate, but the fine particle reactantcould be made up of α-tricalcium phosphate while the coarse particlereactant is made up of β-tricalcium phosphate particles, such that whilethe fine and coarse particle reactants are made up of the same compound,they are made up of different phases of the same compound, where thedifferent phases differ from each other at least in terms of solubility.In yet other embodiments, the different reactants may be made up ofdifferent compounds, e.g., that differ from each other in terms ofmolecular formula, radiopacity, solubility, combinations thereof, etc.For example, in certain embodiments the fine particle reactant is madeup of α-tricalcium phosphate particles, and a coarse particle reactantis made up at least partially of a different calcium containingcompound, e.g., that differs in terms of at least molecular formula, ifnot radiopacity. For example, the coarse particle reactant may include acalcium containing compound that is not a tricalcium phosphate, such asin those embodiments where the coarse particle reactant is made up of acombination of β-tricalcium phosphate particles and particles ofdolomite (CaMgCO₃).

During use, the cement dry reactant component is combined with a settingfluid. Setting fluids of interest vary, and include a variety ofphysiologically compatible fluids, including, but not limited to: water(including purified forms thereof), aqueous alkanol or polyol solutions,e.g., glycerol, where the alkanol or polyol is present in minor amounts,such as less than 20 volume percent; pH buffered or non-bufferedsolutions; solutions of an alkali metal hydroxide, acetate, phosphate orcarbonate, particularly sodium, more particularly sodium phosphate orcarbonate, e.g., at a concentration in the range of 0.01 to 2M, such asfrom 0.05 to 0.5M, and at a pH in the range of 6 to 11, such as from 7to 9, including from 7 to 7.5; and the like.

In some instances, the dry reactant components are combined with asilicate setting fluid, i.e., a setting fluid that is a solution of asoluble silicate. By solution of a soluble silicate is meant an aqueoussolution in which a silicate compound is dissolved and/or suspended. Thesilicate compound may be any compound that is physiologically compatibleand is soluble in water. By soluble in water is meant a concentration of1% or greater, 2% or greater and 5% or greater, where the concentrationof the silicate employed typically ranges from 0-0.1 to 20%, usuallyfrom 0.01-5 to 15% and more usually from 5 to 10%.

Silicates of interest include, but are not limited to: sodium silicates,potassium silicates, borosilicates, magnesium silicates, aluminumsilicates, zirconium silicates, potassium aluminum silicates, magnesiumaluminum silicates, sodium aluminum silicates, sodium methylsilicates,potassium methylsilicates, sodium butylsilicates, sodiumpropylsilicates, lithium propylsilicates, triethanol ammonium silicates,tetramethanolamine silicates, zinc hexafluorosilicate, ammoniumhexafluorosilicate, cobalt hexafluorosilicate, iron hexafluorosilicate,potassium hexafluorosilicate, nickel hexafluorosilicate, bariumhexafluorosilicate, hydroxyammonium hexafluorosilicate, sodiumhexafluorosilicate and calcium fluorosilicate. The preparation of sodiumhexafluorosilicate is described in U.S. Pat. Nos. 4,161,511 and4,160,012; the disclosures of which are herein incorporated by referencein their entirety. Of particular interest in many embodiments aresolutions of sodium silicate, where the manufacture of dry sodiumsilicate (Na₂SiO₃, Na₆Si₂O₇ and Na₂Si₃O₇) is described in Faith, Keyes &Clark's INDUSTRIAL CHEMICALS (1975) pp 755-761.

In certain embodiments, the cements are configured to provide for thepresence of cyclodextrin in the composition prepared from the dryreactants and the setting fluid. Depending on the desired format, thecyclodextrin may be present in the dry reactants or in the settingfluid. By cyclodextrin is meant a cyclic oligosaccharide or mixture ofcyclic oligosaccharides, composed of 5 or more α-D-glucopyranoside unitsthat exhibit a 1->4 linkage. Cyclodextrins of interest includeα-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. The amount ofcyclodextrin that is present in either the liquid or dry components mayvary, depending on the amount that is desired in the flowablecomposition produced therefrom. In some instances, the amount ofcyclodextrin that is desired in the flowable composition produced uponcombination of the dry reactants and setting fluid ranges from 0.01 to10% (w/w), such as 0.05 to 2.0% (w/w). In some instances where thecyclodextrin is present in the dry reactant component, the amount ofcyclodextrin that is present in the dry reactant component ranges from0.01 to 10% by weight, such as 0.05 to 2.0% by weight. Further detailsregarding such embodiments are provided in U.S. application Ser. No.12/568,531; the disclosure of which is herein incorporated by reference.Also encompassed by the present invention are cement embodiments inwhich the coarse particles are those described in PCT application serialno. PCT/US2005/026369 and published as WO/2006/014886 (the disclosure ofwhich is herein incorporated by reference), where the cements furtherinclude a cyclodextrin.

In certain embodiments, the setting fluid may further include an amountof phosphate ion, as described in U.S. Application Publication No.20040250730; the disclosure of which is herein incorporated by referencein its entirety. For example, the concentration of phosphate ion in thesetting fluid may vary, but may be 0.01 mol/L or greater, such 0.02mol/L or greater and including 0.025 mol/L or greater, where theconcentration may range from 0.01 to 0.5, such as from 0.01 to 0.25,including from 0.02 to 0.2 mol/L. The desired phosphate concentrationmay be provided using any convenient phosphate source, such as anon-calcium-containing salt of phosphoric acid that is sufficientlysoluble, e.g., Na₃PO₄, Na₂HPO₄, or NaH₂PO₄. Salts of other cations suchas K⁺, NH₄ ⁺, etc., may also be employed.

In certain embodiments, the cements may further include an amount of anemulsifying agent, as described in U.S. application Ser. No. 11/134,051(published as US 2005-0260279); the disclosure of which is hereinincorporated by reference in its entirety. Emulsifying agents ofinterest include, but are not limited to: polyoxyethylene orpolyoxypropylene polymers or copolymers thereof, such as polyethyleneglycol and polypropylene glycol; nonionic cellulose ethers such asmethylcellulose, ethylcellulose, hydroxymethylcellulose,hydroxyethylcellulose, carboxymethylcellulose, carboxyethylcellulose andhydroxypropylcellulose; additional celluloses, such ascarboxymethylcellulose sodium, carboxymethylcellulose calcium,carboxymethylstarch; polysaccharides produced by microbial fermentation,such as yeast glucans, xanthan gum, β-1,3-glucans (which may bestraight-chained or branched; e.g. curdlan, paramylum, pachyman,scleroglucan, laminaran); other natural polymers, e.g., gum arabic, guargum, carrageenin, gum tragacanth, pectin, starch, gelatin, casein,dextrin, cellulose; polyacrylamide; polyvinyl alcohol; starch; starchphosphate; sodium alginate and propylene glycol alginate; gelatin;amino-containing acrylic acid copolymers and quaternization productsderived therefrom; and the like.

In certain embodiments, the emulsifying agent is a cellulose ether,particularly a nonionic cellulose ether, such as carboxymethylcellulose.Carboxymethylcellulose is available from a variety of commercialsources, including but limited to, Sigma,

Hercules, Fluka and Noviant. In certain embodiments, the averagemolecular weight of the cellulose ether is 1000 daltons or higher, suchas 5000 daltons or higher, where the average molecular weight may be ashigh as 10,000 daltons or higher, e.g., 50,000 daltons or higher,100,000 daltons or higher, and ranges in certain embodiments from 5,000to 100,000 daltons, such as from 10,000 to 50,000 daltons.

The proportion of the emulsifying agent in the cement in certainembodiments ranges from 0.01 to 10% (w/w), such as from 0.05 to 2.0%(w/w).

When employed, the emulsifying agent may be included in one or both ofthe above liquid and dry reactant components.

In certain embodiments, the cement may further include a contrast orimaging agent, where the contrast agent may be present in one or both ofthe liquid and dry components, or separate therefrom until combinationof all of the components to produce the flowable composition. Contrastagents of interest include, but are not limited to: the water solublecontrast agents described in U.S. Pat. No. 7,306,786, the disclosure ofwhich is herein incorporated by reference in its entirety; and thebarium apatite contrast agents described in U.S. application Ser. No.10/851,766 (Published as US20050257714), the disclosure of which isherein incorporated by reference in its entirety.

One or both of the above liquid and dry reactant components may includean active agent that modulates the properties of the product into whichthe flowable composition prepared by the subject method sets. Suchadditional ingredients or agents include, but are not limited to:organic polymers, e.g., proteins, including bone associated proteinswhich impart a number of properties, such as enhancing resorption,angiogenesis, cell entry and proliferation, mineralization, boneformation, growth of osteoclasts and/or osteoblasts, and the like, wherespecific proteins of interest include, but are not limited to:osteonectin, bone sialoproteins (Bsp), α-2HS-glycoproteins, boneGla-protein (Bgp), matrix Gla-protein, bone phosphoglycoprotein, bonephosphoprotein, bone proteoglycan, protolipids, bone morphogenicprotein, cartilage induction factor, platelet derived growth factor,skeletal growth factor, and the like; particulate extenders; inorganicwater soluble salts, e.g., NaCl, calcium sulfate; sugars, e.g., sucrose,fructose and glucose; pharmaceutically active agents, e.g., antibiotics;and the like. Additional active agents of interest include osteoclastinduction agents, e.g., RANKL, as described in U.S. Pat. No. 7,252,833,the disclosure of which is herein incorporated by reference in itsentirety.

To prepare flowable compositions from the dry reactants and settingfluids, suitable amounts of the dry reactants and the setting fluid arecombined to produce a settable or flowable composition. In other words,the ratio of the dry reactants to setting fluid (i.e. the liquid tosolids ratio) is selected to provide for a “settable” or “flowable”composition, where by “settable” or “flowable” composition is meant acomposition that goes from a first non-solid (and also non-gaseous)state to a second, solid state after setting. In some embodiments, theliquid to solids ratio is chosen to provide for a flowable compositionthat has a viscosity ranging from that of milk to that of modeling clay.As such, the liquids to solids ratio employed in the subject methods mayrange from 0.2 to 1.0, such as from 0.3 to 0.6. Of interest in certainembodiments are methods that produce a paste composition, where theliquid to solids ratio employed in such methods may range from 0.25 to0.5, such as from 0.3 to 0.45.

As mentioned above, the requisite amounts of dry reactants and settingfluid are combined under conditions sufficient to produce the flowableproduct composition. As such, the dry and liquid components may becombined under agitation or mixing conditions, such that a homogenouscomposition is produced from the dry and liquid components. Mixing maybe accomplished using any convenient means, including manual mixing asdescribed in U.S. Pat. No. 6,005,162 and automated mixing as describedin WO 98/28068, the disclosures of which are herein incorporated byreference in their entirety. Also of interest is the device disclosed inU.S. Pat. No. 5,980,482, the disclosure of which is herein incorporatedby reference in its entirety. Of interest in certain embodiments are thestorage/mixing elements disclosed in U.S. Pat. Nos. 6,375,935 and6,719,993; as well as U.S. application Ser. No.: 10/462,075 (Publishedas US20040250730); U.S. Pat. No. 7,306,786; U.S. Pat. No. 7,252,833;U.S. application Ser. No. 10/851,766 (Published as US20050257714); U.S.Pat. No. 7,261,717; U.S. Pat. No. 7,252,672; and U.S. Pat. No.7,252,841; the disclosures of which are herein incorporated by referencein their entirety.

The temperature of the environment in which combination or mixing of thedry and liquid components takes place is sufficient to provide for aproduct that has desired setting and strength characteristics, and mayrange from 0 to 50° C., such as from 20 to 30° C. Mixing takes place fora period of time sufficient for a flowable composition to be produced,and may take place for a period of time ranging from 15 to 120 seconds,such as from 15 to 100 seconds and including from 15 to 60 seconds,e.g., 15 to 50 seconds, 15 to 30 seconds, etc.

The above-described protocols result in the production of a flowablecomposition that is capable of setting into a calcium phosphate mineralproduct, as described in greater detail below, where the flowablecomposition is radio-opaque during, at least during implantation.

The flowable compositions produced by the above-described methods arecompositions that set into a biologically compatible, and oftenresorbable and/or remodelable, product, where the product ischaracterized by including calcium phosphate molecules not present inthe initial reactants, i.e., that are the product of a chemical reactionamong the initial reactants.

The term flowable is meant to include paste-like compositions, as wellas more liquid compositions. As such, the viscosity time of the subjectflowable compositions, defined as time periods under which the mixedcomposition injects through a standard Luer-lok fitting after mixing,may range up to 10 minutes, such as up to 7 minutes, including up to 4minutes. Of interest in certain embodiments are paste compositions thathave an injectable viscosity that injects in a time period ranging up to5 minutes, such as up to 4 minutes. Pastes that stay paste-like forlonger period may be displaced by bleeding bone once implanted into thebody, which create a blood interface between the cement and the boneprior to the cement hardening.

The compositions produced by the subject invention set into calciumphosphate mineral containing products. By “calcium phosphate mineralcontaining” product is meant a solid product that includes one or more,usually primarily one, calcium phosphate mineral. In many embodiments,the calcium phosphate mineral is one that is generally poorlycrystalline, so as to be resorbable and, often, remodelable, over timewhen implanted into a physiologically site. The calcium to phosphateratio in the product may vary depending on particular reactants andamounts thereof employed to produce it, but typically range from 2:1 to1.33:1, usually from 1.8:1 to 1.5:1 and more usually from 1:7:1 to1.6:1. Of interest in certain embodiments are apatitic products, whichapatitic products have a calcium to phosphate ratio ranging from 2.0:1to 1.33:1, including both hydroxyapatite and calcium deficient analogsthereof, including carbonate substituted hydroxyapatite (i.e. dahllite),etc. The subject paste-like composition is, in certain embodiments, onethat is capable of setting into a hydroxyapatitic product, such as acarbonated hydroxyapatite, i.e. dahllite, having a carbonatesubstitution of from 2 to 10%, usually from 2 to 8% by weight of thefinal product.

The period of time required for the compositions to harden or “set” mayvary. By set is meant: the Gilmore Needle Test (ASTM C266-89), modifiedwith the cement submerged under 37° C. physiological saline. The settimes of the subject cements may range from 30 seconds to 30 minutes,such as from from 2 to 15 minutes and including from 4 to 12 minutes. Inmany embodiments, the flowable composition sets in a clinically relevantperiod of time. By clinically relevant period of time is meant that thepaste-like composition sets in 20 minutes or less, such as 15 minutes orless and including 10 minutes or less, where the composition remainsflowable for 1 minute or longer, such as 2 minutes or longer, including5 minutes or longer following combination or mixture of the precursorliquid and dry cement components.

In some instances, the compositions rapidly set into a high strengthproduct, as determined by the ASTM C403/C403M-06 modified test describedin the experimental section below. In some instances, the compositionsattain high strength rapidly, such that they may be viewed as rapidstrength attainment compositions. As such, at 4 minutes the compositionsof certain embodiments have a setting value of 1000 Newtons or greater,such as 1200 Newtons or greater, where the setting value may be as highas 1300 or 1400 Newtons or greater. At 6 minutes the compositions mayhave a setting value of 1500 Newtons or greater, such as 1700 Newtons orgreater, including 1800 Newtons or greater, e.g., 1900 Newtons orgreater or 2000 Newtons or greater.

The compressive strength of the product into which the flowablecomposition sets may vary significantly depending on the particularcomponents employed to produce it. Of particular interest in manyembodiments is a product that has a compressive strength sufficient forit to serve as at least a cancellous bone structural material. Bycancellous bone structural material is meant a material that can be usedas a cancellous bone substitute material as it is capable ofwithstanding the physiological compressive loads experienced bycompressive bone under at least normal physiological conditions. Assuch, the subject flowable paste-like material is one that sets into aproduct having a compressive strength of 20 or greater, such as 40 andgreater, and including 50 or greater MPa, as measured by the assaydescribed in Morgan, E F et al., 1997, Mechanical Properties ofCarbonated Apatite Bone Mineral Substitute: Strength, Fracture andFatigue Behavior. J. Materials Science: Materials in Medicine. V. 8, pp559-570, where the compressive strength of the final apatitic productmay be as high as 60 MPa or higher. Compressive strengths can beobtained that range as high 100 to 200 MPa.

The resultant product may have a high tensile strength. Tensile strengthis determined using the protocol described in the experimental sectionbelow, and where the products may exhibit a 24-hour tensile strength of5 MPa or greater, such as 7 MPa or greater, e.g., 7.5 to 8 MPa.

In certain embodiments, the resultant product is stable in vivo forextended periods of time, by which is meant that it does not dissolve ordegrade (exclusive of the remodeling activity of osteoclasts) under invivo conditions, e.g., when implanted into a living being, for extendedperiods of time. In these embodiments, the resultant product may bestable for 4 months or longer, 6 months or longer, 1 year or longer,e.g., 2.5 years, 5 years, etc. In certain embodiments, the resultantproduct is stable in vitro when placed in an aqueous environment forextended periods of time, by which is meant that it does not dissolve ordegrade in an aqueous environment, e.g., when immersed in water, forextended periods of time. In these embodiments, the resultant productmay be stable for 4 months or longer, 6 months or longer, 1 year orlonger, e.g., 2.5 years, 5 years, etc.

In certain embodiments of interest, the product that is produced is acomposite product, which includes some unreacted particles, e.g., fromthe coarse population, present in the final product. In certain of theembodiments where such a cement is implanted into an in vivo site, theunreacted particles may dissolve (e.g., via resorption) over timeleaving a porous structure at the implant site, where the porousstructure remains until it is remodeled. In certain embodiments, theremaining coarse particles in the composite may have a differentradiopacity than the remainder of the product, e.g., where at least aportion of the coarse particles in the cement were dolomite.

In certain embodiments, the flowable paste-like composition is capableof setting in a fluid environment, such as an in vivo environment at abone repair site. As such, the flowable paste composition can set in awet environment, e.g., one that is filled with blood and otherphysiological fluids. Therefore, the site to which the flowablecomposition is administered during use need not be maintained in a drystate.

In certain embodiments, the subject cement compositions may be seededwith any of a variety of cells, as described in published U.S. PatentPublication No. 20020098245, the disclosure of which is hereinincorporated by reference in its entirety.

In addition, in certain embodiments the compositions includedemineralized bone matrix, which may be obtained typically in alyophilized or gel form and is combined with the cement composition atsome prior to implantation. A variety of demineralized bone matrixes areknown to those of skill in the art and any convenient/suitable matrixcomposition may be employed.

In certain embodiments, the cements may include one or more collectionsof contrast particles (for example, for use as tracers during use of thecement), e.g., as described in U.S. Pat. No. 6,273,916 or U.S.application Ser. Nos. 10/629,31 and 10/851,766; the disclosures of whichare herein incorporated by reference in their entirety.

One cement composition in which the tricalcium phosphate coarseparticles of the invention find use is the composition described in PCTapplication serial no. PCT/US2005/026369 and published asWO/2006/014886, the disclosure of which is herein incorporated byreference.

Applications

Flowable compositions produced from cements of the invention, e.g., asdescribed above, find use in applications where it is desired tointroduce a flowable material capable of setting up into a solid calciumphosphate product into a physiological site of interest, such as indental, craniomaxillofacial and orthopedic applications. In orthopedicapplications, the cement may be prepared, as described herein, andintroduced or applied to a bone repair site, such as a bone sitecomprising cancellous and/or cortical bone. In some instances, the siteof application is a cancellous bone void that results from reducing afracture. In these instances, the methods may include reducing a bonefracture and then applying an amount of the flowable composition to theresultant void, where the amount may be sufficient to substantially ifnot completely fill the void.

Orthopedic applications in which the cements prepared by the subjectsystem find use include, but are not limited to, the treatment offractures and/or implant augmentation, in mammalian hosts, particularlyhumans. In such fracture treatment methodologies, the fracture is firstreduced. Following fracture reduction, a flowable structural materialprepared by the subject system is introduced into the cancellous tissuein the fracture region using the delivery device described above.Specific dental, craniomaxillofacial and orthopedic indications in whichthe subject invention finds use include, but are not limited to, thosedescribed in U.S. Pat. No. 6,149,655, the disclosure of which is hereinincorporated by reference in its entirety. In addition to theseparticular applications described in this U.S. Patent, the subjectcement compositions also find use in applications where a sternotomy hasbeen performed. Specifically, the subject cements find use in theclosure process of a sternotomy, where the bone fragments are rejoinedand wired together, and any remaining cracks are filled with the subjectcement. In yet other embodiments, the subject compositions find use indrug delivery, where they are capable of acting as long lasting drugdepots following administration to a physiological site. See e.g. U.S.Pat. Nos. 5,904,718 and 5,968,253; the disclosures of which are hereinincorporated by reference in their entirety.

Representative applications of interest also include, but are notlimited to: those described in U.S. Pat. Nos. 6,375,935 and 6,719,993;as well as U.S. application Ser. No.: 10/462,075 (Published asUS20040250730); U.S. Pat. No. 7,306,786; U.S. Pat. No. 7,252,833; U.S.application Ser. No. 10/851,766 (Published as US20050257714); U.S. Pat.No. 7,261,717; U.S. Pat. No. 7,252,672; and U.S. Pat. No. 7,252,841; thedisclosures of which are herein incorporated by reference in theirentirety.

Kits

Also provided are kits that include the subject cements, where the kitsat least include a dry particulate composition which includes atricalcium phosphate coarse particle composition, as described above.One embodiment provides a kit comprising a setting fluid and a dryreactant component comprising a tricalcium phosphate coarse particlecomposition comprising tricalcium phosphate particles ranging in sizefrom 38 to 212 μm. The coarse particles may include an alkali metal ionin an amount ranging from 1500 to 2500 μm. The kit can also include afine calcium phosphate particulate composition having a mean particlesize of less than 8 μm and narrow particle size distribution.

In certain embodiments, the kits further include a liquid component.When both components are present, the dry and liquid components may bepresent in separate containers in the kit, or some of the components maybe combined into one container, such as a kit wherein the dry componentsare present in a first container and the liquid components are presentin a second container, where the containers may or may not be present ina combined configuration, as described in U.S. Pat. No. 6,149,655, thedisclosure of which is herein incorporated by reference in its entirety.In addition to the cement compositions, the subject kits may furtherinclude a number of additional reagents, e.g., cells (as describedabove, where the composition is to be seeded), protein reagents (asdescribed above), and the like.

In certain embodiments, the kits further include a cyclodextrin, e.g.,as described in U.S. application Ser. No. 12,568,531.

In certain embodiments, the subject cements may be kitted as describedin U.S. Pat. No. 6,273,916, the disclosure of which is hereinincorporated by reference in its entirety, e.g., packaged in a kit withat least two different sterilized pouches (or analogous compartments) ofcement that may independently used at the same or different times, whereeach pouch may include the same or different cement formulation, e.g.,where the cements may differ in terms of contrast characteristics.

In certain embodiments, the kits may further include mixing and/ordelivery elements, e.g., mortar and pestle, spatula, etc., whichelements find use in, e.g., the preparation and/or delivery of thecement composition.

In addition to above-mentioned components, the subject kits typicallyfurther include instructions for using the components of the kit topractice the subject methods. The instructional material may also beinstructional material for using the cement compositions, e.g., it mayprovide surgical techniques and principals for a particular applicationin which the cement is to be employed. The instructions for practicingthe subject methods are generally recorded on a suitable recordingmedium. For example, the instructions may be printed on a substrate,such as paper or plastic, etc. As such, the instructions may be presentin the kits as a package insert, in the labeling of the container of thekit or components thereof (i.e., associated with the packaging orsubpackaging) etc. In other embodiments, the instructions are present asan electronic storage data file present on a suitable computer readablestorage medium, e.g. CD-ROM, diskette, etc. In yet other embodiments,the actual instructions are not present in the kit, but means forobtaining the instructions from a remote source, e.g. via the internet,are provided. An example of this embodiment is a kit that includes a webaddress where the instructions can be viewed and/or from which theinstructions can be downloaded. As with the instructions, this means forobtaining the instructions is recorded on a suitable substrate.

Systems

Also provided are systems that find use in practicing the subjectmethods, as described above. The subject systems at least include dryand liquid components of a cement, as described above, and a mixingelement. In certain embodiments, the systems may further includeadditional agents, e.g., contrast agents, active agents, etc., asdescribed above.

The following examples are offered by way of illustration and not by wayof limitation.

Experimental I. Process of Forming Coarse Particles

Process A provides a preparation method for forming a tricalciumphosphate particulate composition as described in PCT application serialno. PCT/US2005/026369 and published as WO/2006/014886. Process A isprovided as a comparative example for Processes B and C, which processesare embodiments of the coarse particle preparation methods of theinvention.

Process B and Process C provided high yields of coarse particles ascompared to Process A. Both processes yielded particles that are same inphase (95-97% α-TCP, 3-5% HA), have similar morphology (they areirregularly shaped particles) and have no major impurity incorporationbut have different densities and hardness. Process B utilizes a step ofdisc milling after formation of hydroxyapatite. Process C utilizes astep of pelletizing after formation of hydroxyapatite. Table 1 showssteps that are common to Processes A-C. Tables 2-4 show the successivesteps for Processes A-C, respectively.

TABLE 1 Common Steps to Processes A-C Step Description of step 1 Weigh1414.1 g ± 1.0 g DCPA and 520.2 g ± 1.0 g Calcite in a container 2 Blendon jar mill using ‘100’ setting 3 Weigh 1395.2 g ± 1.0 g DI H₂O into abeaker Carefully introduce blended powder into beaker 5 Mix usingblender on low setting 6 Fill tray molds with slurry to depth of ¾inches 7 Place trays in oven at 110° C. 8 Take the trays out and letthem cool to room temperature 9 Place cakes in alumina trays for firing10 Fire the cakes at 1425° C. 11 Quench the cakes with a stainless steelrod 12 Let the quenched material cool to room temperature

TABLE 2 Process A Step Description of step 13 PerformSieving-Grinding-Sieving cycles to reduce particles to appropriate sizes14 The process yields 17% particles of 38-212 μm 185 grams of particlesof 38-212 μm 915 grams of particles of <38 μm

TABLE 3 Process B Step Description of step 13 Put the material into discmill (3 times) at a gap setting of 254 μm in order to obtain <38 μmparticle size 14 Jet Mill above material at a feed rate of 275 to obtain2 μm jet milled impact 15 Place the jet milled powder in the stainlesssteel bucket of the blender 16 Prepare sodium phosphate solution bydissolving 11.445 grams in 336 grams DI H₂O 17 Add the sodium phosphatesolution into the powder and mix (Formation of Hydroxyapatite) 18 Scrapethe paste from the container 19 Dry at 140° C. for 2 hours and cool 20Sieve the powders 21 Disc Mill >212 μm powders at a gap setting of 500μm (Disc Mill) 22 Sieve the disc milled powder 23 Repeat discmill-sieving cycle until all the powder is grinded to <212 μms 24 Firethe powders at 1425° C. for 2 hour (Sintering) 25 Quench the powders bylight pressing by a quencher 26 Sieve the fired powders (Start ofMechanical manipulation) 27 Grind the >212 μm fraction in an aluminamortar 28 Sieve the grinded powders 29 Repeat grinding-sieving processuntil all the powder is <212 μm 30 The process yields 80% particles of38-212 μm 744 grams particles of 38-212 μm 186 grams of waste <38 μm

TABLE 4 Process C Step Description of step 13 Put the material into discmill (3 times) at a gap setting of 254 μm in order to obtain <38 μmparticle size 14 Place the <38 μm powder in the stainless steel bucketof the blender 15 Prepare sodium phosphate solution by dissolving 11.2grams in 465 grams DI H₂O 16 Add the sodium phosphate solution into thepowder and mix (Formation of Hydroxyapatite) 17 Scrape the attachedpaste from the container 18 Dry at 140° C. overnight and cool 19 DiscMill the powders at a gap setting of 1500 μm 20 Send the powders forpellet making (Pelletize) 21 Receive the pellets from pellet making 22Fire the pellets at 1425° C. for 2 hours (Sintering) 23 Quench byspreading the pellets on a stainless steel tray 24 Grind the pellets inthe disc mill at a gap setting of 500 μm (Start of Mechanicalmanipulation) 25 Sieve the disc milled powder 26 Disc mill the >212 μmpowders at a gap setting of 254 μm 27 Sieve the disc milled powder 28Disc mill the >212 μm powders at a gap setting of 254 μm 29 Sieve thedisc milled powder 32 The process yields 60% particles of 38-212 μm 570grams particles of 38-212 μm 380 grams of waste <38 μm

Results

(a) XRD Comparison

FIG. 1 shows X-ray diffraction of the materials synthesized by ProcessA, Process B, and Process C.

Table 5 shows a Rietveld analysis of the materials synthesized byProcess A, Process B, and Process C.

TABLE 5 Rietveld Analysis of Materials Synthesized by Processes A-CSample Alpha-TCP Beta-TCP HA Process A ~95 <1 ~4-5 Process B ~94 <1 ~5-6Process C ~97 <1 ~2-3

(b) FE-SEM Micrographs

FIGS. 2 a and 2 b show morphology of particles formed from Process A.FIG. 2 a shows an SEM micrograph of particles obtained from Process Athat are 38-106 μm. FIG. 2 b shows an SEM micrograph of particlesobtained from Process A that are 106-212 μm. The coarse particles areporous in structure. The coarse particles from Process A are formed whensmall particles loosely bind to each other by forming necks duringsintering. The coarse particles from Process A are weak and are observedto break into 30 μm sized particles during light ultrasonication.

FIG. 3 a shows morphology of calcite. In FIG. 3 a, there is aneedle-shaped morphology. The needles are at an average of 2 μm inlength and 0.25 μm in diameter. FIG. 3 b shows morphology of monetite.In FIG. 3 b, there is a rectangular-shaped plate-like morphology. Thereare different sized crystals.

FIG. 4 shows SEM analysis of particles formed from Process A, after ablending step (step 5). There is a homogeneous mixture of calciteneedles and monetite crystals.

FIGS. 5 a and 5 b show morphology of particles formed from Process B.FIG. 5 a shows an SEM micrograph of particles obtained from Process Bthat are 38-106 μm. FIG. 5 b shows an SEM micrograph of particlesobtained from Process B that are 106-212 μm. The coarse particles arevery dense and strong. The use of coarse particles formed from Process Bin a settable/flowable composition gives higher setting and tensilevalues. For an impact formulation, a tensile strength of around 8 MPa isachieved by coarse particles formed from Process B, whereas a tensilestrength of around 4.5 MPa is achieved by coarse particles formed fromProcess A.

FIG. 6 shows SEM analysis of particles formed from Process B before thefiring step (step 10). In Process B, the cement reaction occurs, thusforming small interlocking needles as seen in high magnification.

FIG. 7 shows SEM analysis of particles formed from Process B after thefiring step (step 10). The coarse particles are dense and can withstandultrasonication without breaking.

FIG. 8 shows SEM analysis of particles formed from Process B after thefiring step (step 10). Only small percentage of surface porosity isformed due to either evaporation of gases or conversion of 4/5 grainsinto 3 grains.

FIGS. 9 a and 9 b show morphology of particles formed from Process C.FIG. 9 a shows an SEM micrograph of particles obtained from Process Cthat are 38-106 μm. FIG. 9 b shows an SEM micrograph of particlesobtained from Process C that are 106-212 μm. The coarse particles arevery dense and strong. The use of coarse particles formed from Process Cin a settable/flowable composition gives higher setting and tensilevalues. The surface area of the particles formed from Process C issimilar to the surface area of the particles formed from Process A.

(c) Inductively Coupled Plasma—Atomic Emission Spectrocopy (ICP-AES)

The ICP-AES analysis in Table 6 shows no major differences in elementalanalysis of the coarse particles from Processes A-C. For the Process Band Process C, only sodium percentage was higher than Process A. Thissodium amount comes from SPMA that was added to a-TCP for converting tohydroxyapatite.

TABLE 6 ICP-AES Analysis of coarse particles synthesized by differentprocesses Process A Process B Process C 38-106 106-212 38-106 106-21238-106 106-212 Element μm μm μm μm μm μm P (%) 20.02 20.1 19.44 19.119.05 19.61 K (%) 0.01 0 0.01 0.01 0.01 0.01 Ca (%) 39.57 40 38.2 37.1338.05 38.04 Mg (%) 0.08 0.08 0.07 0.07 0.12 0.12 Zn (ppm) 7.2588 6.40488.4 6.91 5.8 8.7 Cu (ppm) 0 0 0 0 1.77 1.39 Mn (ppm) 6.1219 6.9635 7.218.22 6.49 10.37 Fe (ppm) 129.63 88.889 108.4 99.78 136.36 157.25 S (%)0.07 0.01 0.002 0 0.01 0.01 Na (ppm) 26.51 27.65 1992 2110 1722 1798 B(ppm) 5.399 6.351 15.27 11.9 10.11 11.18 Al (ppm) 84.36 56.24 116.8115.8 159.95 227.9 N (%) 0 0 0 0 0 0 Si (ppm) 149.5 152 103 112.5 117.597 Zr (ppm) 24 13.5 40.5 34.5 25 11.5

II. Process of Forming Fine Calcium Phosphate Particles

The fine or 2 μm α-TCP is prepared as follows:

-   -   a. Monetite (CaHPO₄) is combined with calcite (CaCO₃)in a ball        mill    -   b. Water is added to this mixture and form a slurry    -   c. The slurry is placed into molds to make wet cakes    -   d. The cakes are fired 1425° C. for 1 hour followed by quenching    -   e. Ball mill and sieve the powder to obtain fractions of <38 μm        α-TCP, 38-106 μm α-TCP, and 106-212 μm α-TCP    -   f. Jet mill <38 μm α-TCP fraction to obtain 2 μm α-TCP

The mean particle size is in the range of 2-3 μm.

III. Test Formulations A. FORMULATION #1

Material Range Average Alpha-cyclodextrin = 0.023-0.027 grams 0.025grams SPMA = 0.104-0.114 grams 0.109 grams 106 − 212 μm α-TCP* =3.070-3.110 grams 3.090 grams 2 μm α-TCP = 6.470-6.490 grams 6.480 gramsTotal average powder weight = 9.704 grams Liquid (dil. Na-silicatesoln.) = 2.990-3.010 grams 3.00 grams Liquid to powder ratio = 0.31

B. FORMULATION #2

Material Range Average Alpha-cyclodextrin = 0.023-0.027 grams 0.025grams CMC = 0.047-0.049 grams 0.048 grams SPMA = 0.068-0.078 grams 0.073grams 38 − 106 μm α-TCP* = 1.506-1.526 grams 1.516 grams 106 − 212 μmαTCP* = 1.506-1.526 grams 1.516 grams 2 μm α-TCP = 6.060-6.080 grams6.070 grams Total average powder weight = 9.248 grams Liquid (dil.Na-silicate soln.) = 2.990-3.010 grams 3.31 grams Liquid to powder ratio= 0.36

III. Control Formulations A. CONTROL FORMULATION #1

Material Range Average SPMA = 0.104-0.114 grams 0.109 grams 106-212 μmα-TCP* = 3.070-3.110 grams 3.090 grams 2 μm α-TCP = 6.470-6.490 grams6.480 grams Total average powder weight = 9.679 grams Liquid (dil.Na-silicate soln.) = 2.990-3.010 grams 3.00 grams Liquid to powder ratio= 0.38

B. CONTROL FORMULATION #2

Material Range Average CMC = 0.047-0.049 grams 0.048 grams SPMA =0.068-0.078 grams 0.073 grams 38-106 μm α-TCP* = 1.506-1.526 grams 1.516grams 106-212 μm α-TCP* = 1.506-1.526 grams 1.516 grams 2 μm α-TCP =6.060-6.080 grams 6.070 grams Total average powder weight = 9.223 gramsLiquid (dd. Na-silicate soln.) =   3.30-3.320 grams 3.31 grams Liquid topowder ratio = 0.42

C. Mixing

For both formulations, the powder and liquid are mixed using a mortarand pestle to produce paste which is then allowed to set and tested asdescribed above.

IV. Setting Strength

A. Methods

A modification of the standard setting test described in ASTMC403/C403M-06 is employed, in which the load required to drive needles aprescribed distance into concrete or a similar setting material ismeasured. The modification involves a needle with a tip configurationsimilar to that used in ASTM C266-07. A modified high load indentor (7mm in diameter) is attached to Instron material testing machine with amaximum load of 5000 N. The needle is pushed 1.25 mm at a rate of 15.2mm/s into the sample cured at 32±0.5° C. and 100% RH. No spring loadaverage is calculated or used in later calculations (the high loadindentor test fixture does not use a spring).

B. Results

An indentation load in excess of 3.5 MPa (135 Newton) has beendetermined as the time of initial setting according to the standard ofASTM C403/C403M-06.

Control Test Form #1 4 min Setting Strength  600N 1700N 6 min SettingStrength 1000N 2200N Form #2 4 min Setting Strength  500N 1400N 6 minSetting Strength  900N 1900N

As can be seen from the above results, inclusion of alpha cyclodextrinsignificantly increases the setting strength as compared to the control.

V. Tensile Strength

A. Methods

The testing was conducted using an Instron mechanical testing system(Canton, Mass.). The test specimens were circular rings of 0.5″ I.D. and0.3″ thickness that were filled with the cement using a spatula. Thefilled molds were placed into a phosphate buffered saline bathmaintained at 37° C. and allowed to cure for 24 hours. Samples were thenremoved from the unit, placed on a steel platen and crushed at a crosshead speed of 0.1 inches/minute. Ultimate tensile stress was calculatedusing the following equation:

Equation of tensile stress: σ=2P/πDt

-   -   where: P=ultimate compressive load, Newtons    -   D=sample diameter, millimeters    -   t=sample thickness, millimeters.

B. Results

Control Test Form #1 24 hr Tensile Strength 4.5 MPa 8 MPa Form #2 24 hrTensile Strength 4.3 MPa 7.5 MPa

As can be seen from the above results, inclusion of alpha cyclodextrinsignificantly increases the tensile strength as compared to the control.

VI. Compressive Strength

A. Methods

The compressive strength test is a modification of ASTM F 451. Theprimary difference from the ASTM method is that pressurization of thevoid filler specimens is not required. Additional modifications to thetest involve curing the bone void filler specimens for 24 hours in a 37°C. phosphate buffered saline environment at pH=7.4 and sanding the endsof the specimens before removing them from the mold for testing. Eachspecimen is placed between the loading platens of the mechanical testingsystem. Specimens are loaded along the longitudinal axis at displacementrate of 0.1 in./min until failure. Load, displacement, and time arerecorded continuously at a sampling rate of 10 Hz.

B. Results

The compressive strength for both test formulation 1 and 2 above wasfound to be 55 MPa.

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

The invention now being fully described, it will be apparent to one ofskill in the art that many changes and modifications can be made theretowithout departing from the spirit and scope of the appended claims.

1-12. (canceled)
 13. A tricalcium phosphate coarse particle compositionproduced according to a method comprising: (a) converting an initialtricalcium phosphate particulate composition to hydroxyapatite; (b)sintering said hydroxyapatite to produce a second tricalcium phosphatecomposition; and (c) mechanically manipulating said second tricalciumphosphate composition to produce the tricalcium phosphate coarseparticle composition.
 14. A tricalcium phosphate coarse particlecomposition comprising tricalcium phosphate particles ranging in sizefrom 38 to 212 μm, wherein said particles comprise sodium in an amountranging from 1500 to 2500 ppm.
 15. A method of producing a flowablecomposition that sets into a calcium phosphate containing product, saidmethod comprising: combining: (a) a setting fluid; and (b) a dryreactant component comprising a tricalcium phosphate coarse particlecomposition comprising tricalcium phosphate particles ranging in sizefrom 38 to 212 μm, wherein said particles comprise sodium in an amountranging from 1500 to 2500 ppm; in a ratio sufficient to produce saidflowable material.
 16. The method according to claim 15, wherein saiddry reactant component comprises a fine calcium phosphate particulatecomposition having a mean particle size of less than 8 μm and narrowparticle size distribution.
 17. The method according to claim 16,wherein the ratio of said line to coarse compositions in said dryreactant component ranges from 1 to
 10. 18. The method according toclaim 15, wherein at least one of said setting fluid and dry reactantscomprises a cyclodextrin.
 19. A flowable composition that sets into acalcium phosphate containing product, wherein said composition isproduced by the method according to claim
 15. 20. The compositionaccording to claim 20, wherein said composition comprises acyclodextrin.
 21. A method of repairing a hard tissue defect, saidmethod comprising: applying to the site of said defect allowablecomposition that sets into a calcium phosphate containing product,wherein said composition is produced by the method according to claim15. 22-24. (canceled)